γ-分泌酶抑制剂(LY411575)的合成工艺研究

doi:10.7503/cjcu20160742

摘要/Abstract

摘要：

对γ-分泌酶抑制剂(LY411575)的合成路线进行改进, 新合成路线下该化合物的总收率为35%, 比文献方法提高了16%; 对关键中间体提前进行了手性拆分, 从而使在制备最终产品的后3步反应中用到的原料减少了50%, 降低了反应成本和最终产品的纯化难度. 另外, 对拆分过程中的主要因子进行了单因素实验, 考察了各因素对产品的e.e.值和反应收率的影响. 获得了最佳反应条件: D-(+)-二对甲基苯甲酰酒石酸为拆分试剂, 甲醇作溶剂, 加热到回流溶解, 加入的溶剂量为每g底物12 mL, 从回流降到室温所用时间控制在120 min, 拆分的收率为40%, e.e.值为99%.

关键词: 阿尔茨海默病, γ-分泌酶, 关键中间体, 抑制剂

Abstract:

The original synthetic route of gamma secretase inhibitors(LY411575) was improved, the yield of 35% was achieved which increased by 16% compared with the traditional process. Meanwhile, key interme-diates were resolved by chiral acid in advance so that the consumption of raw materials in latter three steps of synthetic process was decreased by 50%. The method contributed to decrease the reaction cost and the difficulty of product purification. In addition, the single-factor experiment was conducted for main factors affected the resolving process to study the influence of various factors on the e.e. value and the yield of products. The optimal reaction condition was obtained as follows: D-(+)-2 methyl benzoyl tartaric acid as the resolution agent, methanol as the solvent, heated to reflux for dissolution, the solvent of 12 mL per gram substrate, the time from the initial temperature of reflux to room temperature controlled in 120 min, the resolution yield of 40% and the e.e. value of 99%.

Key words: Alzheimer’s disease(AD), γ-Secretase, Key intermediate, Inhibitor

中图分类号:

O621.25

TrendMD:

郭宏垚, 李冬, 雷雄, 张旭, 许人军, 王锋, 李稳宏. γ-分泌酶抑制剂(LY411575)的合成工艺研究. 高等学校化学学报, 2017, 38(2): 200.

GUO Hongyao, LI Dong, LEI Xiong, ZHANG Xu, XU Renjun, WANG Feng, LI Wenhong. Synthesis Process Research of γ-Secretase Inhibitors(LY411575)^†. Chem. J. Chinese Universities, 2017, 38(2): 200.

图/表 8

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Solvent	D-(+)-2 Methyl benzoyl tartaric acid		D-Malic acid		L-Mandelic acid		D-Tartaric acid		D-Ethyl diketone tartaric acid		L-Camphors ulfonic acid
Solvent	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)
Methanol	88	49	<5	—	<5	—	7	—	15	73	<5	—
Acetonitrile	39	62	<5	—	<5	—	<5	—	12	68	<5	—

Solvent	D-(+)-2 Methyl benzoyl tartaric acid		D-Malic acid		L-Mandelic acid		D-Tartaric acid		D-Ethyl diketone tartaric acid		L-Camphors ulfonic acid
Solvent	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)
Methanol	88	49	<5	—	<5	—	7	—	15	73	<5	—
Acetonitrile	39	62	<5	—	<5	—	<5	—	12	68	<5	—

Solvent	Methanol	Acetonitrile	Ethyl alcohol
e.e.(%)	88	39	59
Yield(%)	49	62	51

Solvent	Methanol	Acetonitrile	Ethyl alcohol
e.e.(%)	88	39	59
Yield(%)	49	62	51

t/℃	64.5(reflux)	70	80	90
e.e.(%)	88	87	89	88
Yield(%)	49	48	49	47